Chronic alcohol exposure causes the development and maintenance of fatty liver by interfering hepatic fat disposal. Adiponectin, an adipokine predominantly secreted by adipose tissue, plays a central role in the regulation of energy metabolism, lipid and carbohydrate metabolism. Accumulated evidence suggests that down- regulation of adiponectin production has patho-physiological importance in the process of alcoholic fatty liver disease; however, the underlying mechanisms are still elusive. Abnormal hepatic methionine/homocysteine metabolism and hyperhomocysteinemia induced by prolonged alcohol exposure has been reported both in clinical and experimental studies, however, the occurrence of this abnormality in adipose tissue, as well as its potential implication in the regulation of adipose tissue function, specifically adiponectin expression and secretion, has received very few attention. It is our hypothesis that chronic alcohol exposure induces abnormal methionine/homocysteine metabolism not only in the liver, but also in the adipose tissue. Furthermore, we hypothesize that increased accumulation of homocysteine in the adipocytes, either via alcohol-induced endogenous alteration in methionine/homocysteine metabolism or a cross-talk from the liver; contribute to the suppression of adiponectin gene expression and secretion in alcoholic liver disease (ALD). In this proposal, we will utilize both animal and cell culture models to evaluate excessive accumulation of homocysteine in the adipocytes by chronic alcohol feeding as a mechanism for decreased adiponectin gene expression, protein production and secretion. The specific objectives of this project are as follows: 1. Further document the effects of chronic alcohol consumption on methionine/homocysteine metabolism in adipose tissues and explore potential mechanisms involved in this process; 2. Determine the effects of increased homocysteine accumulation in adipocytes on adiponectin production and its causal role in the inhibitory effects of chronic alcohol exposure on adiponectin production in ALD; 3. Elucidate mechanisms whereby homocysteine modulates adiponectin production. The beneficial effects of nutritional intervention, specifically these being able to rectify abnormal methionine/homocysteine metabolism such as betaine and S-adenosylmethionine, have been well-accepted; thus, our approach is designed to not only more completely understand the mechanisms of ALD, but also to develop new therapeutic interventions. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Alcoholic liver disease (ALD) remains an important health problem in the United States. Adiponectin is a soluble mediator predominantly secreted by adipose tissue and in possession of properties of anti-steatosis, anti-inflammation, and anti-fibrosis. Chronic alcohol exposure results in suppressed adiponectin production, which plays an important role in the pathogenesis of ALD. Based on our preliminary findings that chronic alcohol feeding caused elevation of homocysteine levels in the adipose tissue and homocysteine decreased adiponectin production by primary adipocytes, we propose here that altered methionine/homocysteine metabolism both in the liver and in the adipose tissue may play a mechanistic role in the suppression of adiponectin production in ALD. We will use the state-of-the-art technologies to investigate this clinically relevant process.